Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders

Morten Scheibye-Knudsen; Evandro Fei Fang; Deborah L. Croteau; Vilhelm A. Bohr

doi:10.4161/auto.29321

Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders

Morten Scheibye-Knudsen, Evandro Fei Fang, Deborah L. Croteau, Vilhelm A. Bohr^*

^*Corresponding author for this work

30 Citations (Scopus)

Abstract

DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD + (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.

Original language	English
Journal	Autophagy
Volume	10
Issue number	8
Pages (from-to)	1468-1469
Number of pages	2
ISSN	1554-8627
DOIs	https://doi.org/10.4161/auto.29321
Publication status	Published - 2014
Externally published	Yes

Keywords

Autophagy
DNA repair
Mitophagy
SIRT1
Xeroderma pigmentosum group A

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders",

abstract = "DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD + (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.",

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volume = "10",

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T1 - Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders

AU - Scheibye-Knudsen, Morten

AU - Fang, Evandro Fei

AU - Croteau, Deborah L.

AU - Bohr, Vilhelm A.

PY - 2014

Y1 - 2014

N2 - DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD + (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.

AB - DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD + (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.

KW - Autophagy

KW - DNA repair

KW - Mitophagy

KW - SIRT1

KW - Xeroderma pigmentosum group A

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JO - Autophagy

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Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders

Abstract

Keywords

UN SDGs

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